SIX6

Chr 14AR

SIX homeobox 6

Also known as: MCOPCT2, ODRMD, OPTX2, Six9

NCBI Gene: 4990 ENSG00000184302 UniProt: O95475 OMIM: 606326

SIX6 encodes a homeobox transcription factor involved in eye development. Biallelic mutations cause optic disc anomalies with retinal and/or macular dystrophy, inherited in an autosomal recessive pattern. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.595), consistent with its role in ocular development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a homeobox protein that is similar to the Drosophila 'sine oculis' gene product. This gene is found in a cluster of related genes on chromosome 14 and is thought to be involved in eye development. Defects in this gene are a cause of isolated microphthalmia with cataract type 2 (MCOPCT2). [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Optic disc anomalies with retinal and/or macular dystrophyMIM #212550

UniProtOptic disk anomalies with retinal and/or macular dystrophy

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Optic disc anomalies with retinal and/or macular dystrophy; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.59

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.518

Z-score 2.44

OE 0.19 (0.08–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.71Z-score

OE missense 0.83 (0.71–0.97)

117 obs / 140.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.19 (0.08–0.59)

0≤0.351.4

Missense OE?0.83 (0.71–0.97)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 2 / 10.6Missense obs/exp: 117 / 140.8Syn Z: 0.94

Background carrier burden — how many people carry a rare variant somewhere in SIX6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 240

326 rare PASS variants

Rare truncating (LoF)

1 in 8,000

37 rare PASS variants

Rare synonymous (reference)

1 in 290

138 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SIX6. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 310	1 in 6,700
South Asian	~43k	1 in 380	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 260	1 in 6,000
European (Finnish)	~27k	1 in 680	1 in 2,700
Admixed American	~22k	1 in 450	1 in 3,700
African / African American	~21k	1 in 180	≈ 1 in 5,500
East Asian	~20k	1 in 480	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 1,200	none seen
Middle Eastern	~2,884	1 in 180	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓